Abstract The most common cause of irreversible blindness in the elderly population in industrialized countries is age-related macular degeneration (AMD). Degeneration of retinal pigment epithelium (RPE) cells in association with oxidative stress and inflammation is a key hallmark of AMD. However, the detailed molecular mechanisms underlying AMD remain largely unknown and no effective treatment exists for the early or late atrophic stages of the disease. Oxidative stress affecting the physiological function and leading to focal loss of the RPE cells has been suggested to be an important factor contributing to geographic atrophy and vision loss in AMD. Thus implying that limiting the formation of reactive oxygen species within the RPE may effectively prevent or reduce RPE dysfunction observed in AMD patients. This proposal seeks to understand how DJ-1, a multifunctional protein with an antioxidant function, regulates oxidative stress responses in RPE cells. We have observed increased amounts of the functional inactive sulfonic oxidized DJ-1 in the RPE of AMD donors as well as in a mouse model of acute RPE degeneration due to oxidative stress. These findings provide a solid clinical foundation for pursuing studies on the antioxidant mechanisms regulated by DJ-1 in RPE cells. Based on our preliminary data we reasoned of a possible mechanistic pathway via which RPE degeneration results from overall low levels of native DJ-1 or posttranslational modifications (PTMs) that impair its function. The three overlapping areas to be investigated in this project are: 1- To test the hypothesis that RPE degeneration due to oxidative stress is regulated by antioxidant function of DJ-1; 2- To test the hypothesis that mitochondria dysfunction of the RPE due to oxidative stress is regulated by DJ-1; 3- To test the therapeutic potential of DJ-1. We will evaluate the effectiveness of DJ-1 to protect RPE in vivo, in two oxidative stress relevant pre-clinical mice models: an acute RPE degeneration model and a chronic model that generates AMD-like lesions in the outer retina. The methods utilized in this research project include establishment of human and mouse primary RPE cell cultures, immunoprecipitation, immunostaining, live cell imaging, confocal microscopy, animal models of RPE degeneration, scanning laser ophthalmoscopy, spectral-domain optical coherence tomography and electroretinograms.